Participation of Hypertension Patients in Early‐Phase Clinical Trials

Human pharmacology trials (more commonly referred to as phase I trials) are the means by which we collect information concerning an investigational drug's safety, pharmacokinetic (PK) profile, possible drug‐drug interactions, and an estimation of pharmacodynamic (PD) activity.1 Pharmacology studies are conducted across the whole drug development spectrum. By definition, first‐in‐human (FIH), single‐ascending dose, multiple‐ascending dose, and exploratory PK studies are conducted in the earliest phase of a drug's development. Phase I pharmacology studies, however, are often done with compounds that are in later (ie, phase II or III) phases of development, or even after a drug has been approved for marketing. Drug‐drug interaction studies are a good example of a type of phase I pharmacology study that is often completed when a compound is already well on its way to a registration submission, eg, a New Drug Application in the United States or a Marketing Authorisation Application in the European Union.

Traditionally, for most phase I studies we recruit healthy adults. In some instances, individuals with a specific clinical condition are needed in phase I studies. In this regard, patients with renal or hepatic impairment are often included to understand the impact of these conditions on the metabolism and/or clearance of investigational drugs. Another example in which patients are most appropriate for phase I studies concerns the development of potentially cytotoxic drugs for oncology indications: the risks inherent in such experimental drugs make it unethical to administer certain types of molecules to healthy adults.

In recent years, development of compounds targeting increasingly complex biological pathways has led to inclusion of more patient populations in phase I clinical trials. In some cases, the potential adverse effects of a biological agent may preclude its testing in a healthy population, in a manner analogous to oncology drug development. New therapeutic targets for the treatment of diabetes, for example, may induce profound and dangerous levels of hypoglycemia in healthy adults, whereas the effects are modest and salutary in patients. It may also be appropriate to study PD effects in patient populations in early‐phase clinical trials when a biomarker of interest would be expected to be impacted only in such a population. For example, understanding the characteristics of inhibitors of tumor necrosis factors or other proinflammatory cytokines may require their administration to patients with elevations in concentrations of these biomarkers.

This commentary discusses the participation of individuals with hypertension in early‐phase clinical trials. We have noted earlier that we hope that physicians who have not previously been investigators/principal investigators at sites running clinical trials might consider doing so in the future.1 An extension of this involvement in clinical research is for physicians to learn more about how their patients might participate in clinical research should they wish to do so, and how to facilitate such participation.

Human Pharmacology Studies and Hypertension

As noted earlier, there are several human pharmacology core studies necessary to progress or complement later‐phase investigations: these are outlined in the Table1.2, 3

Table 1.

Core Human Pharmacology Studies

Study	Description	What Do the Participants Help Us Understand?	When Does the Study Stop?	So What Is New?
Single‐ascending dose (SAD) studies	Participants receive a single dose. Data are analyzed, safety is assessed, and then, if considered appropriate, another cohort of participants is administered a single, but higher dose. At least one participant usually receives placebo at each dose level	How fast the drug enters the blood stream, how long it takes to clear a single dose from the body, what is the mechanism of excretion, and what adverse events (AEs) are detected	The study protocol precisely specifies the “stopping criteria.” Such criteria may be based on AEs of particular interest, laboratory test results, or a combination	Utilization of pharmacogenomics for information about a drug's dose effect: Does the drug have any dose‐dependent effect on gene expression that may offer clues to dosing in patient studies?
Multiple‐ascending dose (MAD) studies	Participants receive a dose of the drug multiple times over a given period of time, with the dose increasing in subsequent cohorts	At what intervals and for how long a drug needs to be taken to achieve a steady‐state concentration in the plasma. Associated AEs that may emerge with longer drug exposure, as compared with the SAD study	See above	In addition to routine biomarkers (eg, systolic and diastolic blood pressure, pulse wave velocity), novel biomarkers are being utilized to determine safety and efficacy
Food Effect Study	Participants are administered the drug with or without food to determine how drug absorption changes with a meal. These are often conducted in parallel with the MAD study	Does food consumed with the medication change the amount and/or speed at which the drug enters the participant's bloodstream?	See above	Routinely conducted as part of a more complex set of studies involving SAD and MAD studies
Asian Bridging Study	Studies in Asian populations are often needed because of the significant differences in drug metabolism between Asian and Western populations	Does the recommended dosing regimen transfer to other populations that have been shown historically to metabolize certain drugs differently?	See above	Chang and colleagues2 recently discovered that a common mitochondrial aldehyde dehydrogenase 2 (ALDH2) genetic polymorphism predicts development of hypertension in East Asian populations in relation to alcohol consumption. This finding underscores the importance of Asian bridging studies to ensure patient safety globally
Special populations	Dosing of elderly, pediatric, and hepatic‐ or renal‐impaired participants. Primarily for evaluation of pharmacokinetics and safety in populations outside the norms of absorption, metabolism, and excretion	Do elderly or pediatric volunteers absorb and/or metabolize the drug differently? How will hepatic‐ or renal‐impaired patients metabolize the drug?	See above	Ferguson and Flynn3 noted that the incidence of hypertension and prehypertension in American children is rising (2‐fold in the past 2 decades). The need for more pediatric‐specific antihypertensives may be a necessity as obesity rates climb. However, it should be noted that pediatric hypertension studies may not be as rare as one would think3

Most investigational drugs intended for use in hypertension will be tested in the earliest phase of drug development in cohorts of healthy adults. However, for compounds that directly modulate natriuretic peptides (NPs), a PK study that investigates the relationship between drug levels, NP levels, and blood pressure could be an early‐phase clinical trial that would be appropriately conducted in patients. An early‐phase clinical trial conducted in patients presents an important opportunity for investigators: these trials are small in sample size and therefore it is less cost‐prohibitive to explore a broader approach to safety and efficacy in studies employing participants with the disease of interest. Such an approach may facilitate utilization of a broader biomarker effort, pharmacogenomic assessments,2, 4 assaying fluids for analytes such as cytokines,5 and more extensive cardiovascular monitoring such as 24‐hour ambulatory blood pressure monitoring.6 For example, plasma biomarkers, glucose, insulin, C‐reactive protein, and 25‐hydroxyvitamin D5 are all able to produce an early picture of a PD effect before a phase II trial is initiated. This may also be the case for assays measuring the adipokine apelin and the protein hormone relaxin. Papadopoulos and colleagues7 reported that patients with masked hypertension produce significantly lower amounts of these mediators. Pharmacogenomics is also growing in value for investigators. Wilson and colleagues4 reported that a polymorphism in the gene coding for the enzyme methylenetetrahydrofolate reductase can be utilized to target hypertension patients for treatment with riboflavin with significant positive results.

Pharmacogenomics can also be exploited to characterize baseline gene expression in healthy individuals for later comparison during patient trials, potentially providing the answer to whether a treatment also returns some gene expression parameters back to values measured in healthy individuals. Plasma is also biobanked to provide a reference for baseline biomarker data.

Drug‐Drug Interaction Studies

The types of drug‐drug interaction (DDI) studies conducted during clinical development are often dictated by the results of earlier nonclinical in vitro studies. These nonclinical DDI experiments inform investigators as to the potential of a drug to increase or decrease the metabolism of different classes of drugs far in advance of any human trials.

Clinical DDI studies for new antihypertensive drugs are conducted during a later phase of development but are performed in phase I units. These studies evaluate whether any drug interactions are of a large enough magnitude to require adjustments in the dosage or formulation of a drug(s) that might be used concomitantly. For example, 20 mg/d of paroxetine increases the mean area under the plasma concentration‐time curve for both immediate‐release and extended‐release formulations of metoprolol. Based on these data and other pharmacodynamic data, the extended‐release formulation may decrease the risk of adverse events.8

DDI studies are also performed to determine whether any drug interactions require additional therapeutic monitoring or whether there should be a contraindication to concomitant use. For example, the drug mibefradil (similar to verapamil and diltiazem) was withdrawn from the market because it decreased the metabolism of simvastatin, increasing the risk of rhabdomyolysis.9

Maximizing Safety of Participants in Early‐Phase Studies

Because no animal model employed in nonclinical research perfectly predicts human response to a pharmaceutical agent, there is always the possibility that serious safety issues can arise in FIH trials. One often‐cited example is the life‐threatening cytokine‐release syndrome experienced by 6 participants in a phase I clinical trial following administration of the CD28 super‐agonist antibody TGN1412. Since that occurrence in March 2006, additional safeguards have been recommended and widely adopted.10, 11, 12

Early‐phase clinical studies are conducted according to Good Clinical Practices, a comprehensive set of guidelines agreed upon by the International Conference on Harmonisation. Additional regulatory requirements are specified by regional and/or national regulatory bodies. For example, studies in the United States are subject to its Food and Drug Administration's regulations, and studies conducted in the United Kingdom are subject to regulations from the European Medicines Agency as well as the UK Medicines and Healthcare Products Regulatory Agency. Studies must also be approved by an institutional review board (IRB) or ethics committee (EC) to ensure that the study protocol is ethical and that the rights, safety, and well‐being of potential study participants are safeguarded.

Early‐phase studies are typically conducted in clinical pharmacology units. If not located inside a tertiary care hospital with all the emergency response capabilities of a large hospital, these units are routinely situated close to local emergency departments and are notified before dosing with a new compound starts. The principal investigator and research nursing staff all routinely and extensively train for emergency scenarios. It is routine procedure that participants in a clinical trial stay for one or more overnight visits in the clinical pharmacology unit before returning for follow‐up visits.

A strategy called sentinel dosing is often practiced so that one person in the first cohort of participants is dosed in advance of the full study. This ensures that if adverse events manifest quickly, as few participants as possible are impacted. Unfortunately, in the case of the TGN1412 study, all participants in the first‐dose cohort were dosed within minutes of each other. Those who received the active drug became seriously ill almost simultaneously, requiring the transfer of several of them to the intensive care unit.

Study teams within the clinical pharmacology unit also have a responsibility to safeguard participant safety and well‐being. Some organizations (ask before you consider having your patients participate) utilize formalized risk mitigation plans such as Failure Modes Effects Analysis (FMEA). In FMEA, a study protocol's operational and safety risks are reviewed prior to study conduct. These risks are prioritized and a mitigation plan is executed for each potential risk prior to study initiation. The benefit of this system is that it creates a self‐learning, self‐improving team structure within the clinical pharmacology unit. Participants are exposed to less risk and data integrity is also safeguarded.

Patient Recruitment

Patient recruitment strategies embrace traditional print and broadcast media, but now also include social media and online advertising. These new media are still under the same constraints regarding IRB‐ or EC‐approved recruitment material as the more traditional methods of advertising, and targeting of economically disadvantaged members of society or specific segments of the population is forbidden. Remuneration of individuals for participation in studies is reviewed by the IRB or EC. Remuneration should be proportional to the time, effort, and inconvenience required, but must not provide undue inducement to participate.

Increasingly, physician referrals are becoming more essential for the conduct of phase I clinical trials. Therefore, primary care physicians are more likely to be approached by patient recruitment personnel based at their local clinical pharmacology unit. The availability of clinical research opportunities can be very positive within a patient community. Patients are most likely to participate in clinical research when they learn of the opportunity and are counseled by their physician.

In some cases, further efforts are made to connect physicians with the data acquired from their patients during the trial when these data could support the physicians' efforts to better manage their patients' hypertension. All of these changes will necessitate continued effective communication with physicians about the nature of the study, potential impact on concomitant medications, and therapeutic targets, as well as logistics of the study such as procedures involved, number of overnights in the unit, and the number of follow‐up visits.

Disclosures

The authors report no specific funding in relation to the preparation of this paper. No editorial support was used.